Glycosides of Cistanche(GC)is a preparation used extensively for its neuroprotective effect against neurological diseases,but its mechanisms of action remains incompletely understood.Here,we established a bilateral ...Glycosides of Cistanche(GC)is a preparation used extensively for its neuroprotective effect against neurological diseases,but its mechanisms of action remains incompletely understood.Here,we established a bilateral common carotid artery occlusion model of vascular dementia in rats and injected the model rats with a suspension of GC(10 mg/kg/day,intraperitoneally)for 14 consecutive days.Immunohistochemistry showed that GC significantly reduced p-tau and amyloid beta(Aβ)immunoreactivity in the hippocampus of the model rats.Proteomic analysis demonstrated upregulation of mitochondrial precursor protein and downregulation of keratin type II cytoskeletal6A after GC treatment compared with model rats that had received saline.Western blot assay confirmed these findings.Our results suggest that the neuroprotective effect of GC in vascular dementia occurs via the promotion of neuronal cytoskeleton regeneration.展开更多
The B-cell lymphoma 2 (Bcl2) family of proteins participates in cell death or survival through a mitochondrial pathway. The pro-apoptotic members of the Bcl2 family such as Bim, Bid, Bax and Bak trigger cell death b...The B-cell lymphoma 2 (Bcl2) family of proteins participates in cell death or survival through a mitochondrial pathway. The pro-apoptotic members of the Bcl2 family such as Bim, Bid, Bax and Bak trigger cell death by contributing to the enhancement of mitochondrial outer membrane permeabil- ity to pro-apoptotic factors such as cytochrome c, with the subsequent activation of caspases. The anti-apoptotic mem- bers, such as B-cell lymphoma-extra large (Bd-xL), block the pro-apoptotic Bcl2 members and prevent cell death. Bcl-xL is abundantly expressed during development and in mature neurons, suggesting that it plays a role in protection from death from untoward events occurring in adult life such as ischemia, inflammation or trauma. When these neurotoxic in- sults occur, Bcl-xL translocates to mitochondria and prevents activation and homo-oligomerization of pro-apoptotic family members such Bax and Bak. Numerous studies have shown pro-survival roles for Bcl-xL in adult neurons using various models; nevertheless, the role of Bcl-xL outside of the field of neuronal death, i.e., in adult neuronal growth, excitability or synaptic plasticity, has not been studied in depth.展开更多
The mitochondrial unfolded protein response(UPRmt)is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress.Under physiological and pathological conditions,the UPRmt is t...The mitochondrial unfolded protein response(UPRmt)is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress.Under physiological and pathological conditions,the UPRmt is the key to maintaining intracellular homeostasis and proteostasis.Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development,metabolism,and immune processes.UPRmt dysfunction leads to a variety of pathologies,including cancer,inflammation,neurodegenerative disease,metabolic disease,and immune disease.Stem cells have a special ability to selfrenew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues.These cells are involved in development,tissue renewal,and some disease processes.Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported,the roles of the UPRmt in stem cells are not fully understood.The roles and functions of the UPRmt depend on stem cell type.Therefore,this paper summarizes the potential significance of the UPRmt in embryonic stem cells,tissue stem cells,tumor stem cells,and induced pluripotent stem cells.The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.展开更多
BACKGROUND Gastric carcinoma(GC)is a common gastrointestinal malignancy worldwide.Based on the cancer-related mortality,the current prevention and treatment strategies for GC still show poor clinical results.Therefore...BACKGROUND Gastric carcinoma(GC)is a common gastrointestinal malignancy worldwide.Based on the cancer-related mortality,the current prevention and treatment strategies for GC still show poor clinical results.Therefore,it is important to find effective drug treatment targets.AIM To explore the mechanism by which 18β-glycyrrhetinic acid(18β-GRA)regulates mitochondrial ribosomal protein L35(MRPL35)related signal proteins to inhibit the proliferation of GC cells.METHODS Cell counting kit-8 assay was used to detect the effects of 18β-GRA on the survival rate of human normal gastric mucosal cell line GES-1 and the proliferation of GC cell lines MGC80-3 and BGC-823.The apoptosis and cell cycle were assessed by flow cytometry.Cell invasion and migration were evaluated by Transwell assay,and cell scratch test was used to detect cell migration.Furthermore,a tumor model was established by hypodermic injection of 2.5×106 BGC-823 cells at the selected positions of BALB/c nude mice to determine the effect of 18β-GRA on GC cell proliferation,and quantitative reverse transcription-polymerase chain reaction(qRT-PCR)was used to detect MRPL35 expression in the engrafted tumors in mice.We used the term tandem mass tag(TMT)labeling combined with liquid chromatography–tandem mass spectrometry to screen for differentially expressed proteins(DEPs)extracted from GC cells and control cells after 18β-GRA intervention.A detailed bioinformatics analysis of these DEPs was performed,including Gene Ontology annotation and enrichment analysis,Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis,and so on.Moreover,STRING database(https://string-db.org/)was used to predict proteinprotein interaction(PPI)relationships and Western blot was used to detect the expression of proteins of interest in GC cells.RESULTS The results indicated that 18β-GRA could inhibit the proliferation of GC cells in a dose-and timedependent manner.It could induce GC cell apoptosis and arrest the cell cycle at G0/G1 phase.The proportion of cells arrested at S phase decreased with the increase of 18-GRA dose,and the migration and invasiveness of GC cells were inhibited.The results of animal experiments showed that 18β-GRA could inhibit tumor formation in BALB/c nude mice,and qRT-PCR results showed that MRPL35 expression level was significantly reduced in the engrafted tumors in mice.Using TMT technology,609 DEPs,among which 335 were up-regulated and 274 were down-regulated,were identified in 18β-GRA intervention compared with control.We found that the intervention of 18β-GRA in GC cells involved many important biological processes and signaling pathways,such as cellular processes,biological regulation,and TP53 signaling pathway.Notably,after the drug intervention,MRPL35 expression was significantly down-regulated(P=0.000247),TP53 expression was up-regulated(P=0.02676),and BCL2L1 was down-regulated(P=0.01699).Combined with the Retrieval of Interacting Genes/Proteins database,we analyzed the relationship between MRPL35,TP53,and BCL2L1 signaling proteins,and we found that COPS5,BAX,and BAD proteins can form a PPI network with MRPL35,TP53,and BCL2L1.Western blot analysis confirmed the intervention effect of 18β-GRA on GC cells,MRPL35,TP53,and BCL2L1 showed dose-dependent up/down-regulation,and the expression of COPS5,BAX,and BAD also increased/decreased with the change of 18β-GRA concentration.CONCLUSION 18β-GRA can inhibit the proliferation of GC cells by regulating MRPL35,COPS5,TP53,BCL2L1,BAX,and BAD.展开更多
Mammalian mitochondria have small genomes encoding very limited numbers of proteins.Over one thousand proteins and noncoding RNAs encoded by the nuclear genome must be imported from the cytosol into the mitochondria.H...Mammalian mitochondria have small genomes encoding very limited numbers of proteins.Over one thousand proteins and noncoding RNAs encoded by the nuclear genome must be imported from the cytosol into the mitochondria.Here,we report the identification of hundreds of circular RNAs(mecciRNAs)encoded by the mitochondrial genome.We provide both in vitro and in vivo evidence to show that mecciRNAs facilitate the mitochondrial entry of nuclear-encoded proteins by serving as molecular chaperones in the folding of imported proteins.Known components involved in mitochondrial protein and RNA importation,such as TOM40 and PNPASE,interact with mecciRNAs and regulate protein entry.The expression of mecciRNAs is regulated,and these transcripts are critical for the adaption of mitochondria to physiological conditions and diseases such as stresses and cancers by modulating mitochondrial protein importation.mecciRNAs and their associated physiological roles add categories and functions to the known eukaryotic circular RNAs and shed novel light on the communication between mitochondria and the nucleus.展开更多
Reactive oxygen species(ROS) are free radicals thought to mediate the neurotoxic effects of several neurodegenerative disorders.In the central nervous system,ROS can also trigger a phenotypic switch in both astrocyt...Reactive oxygen species(ROS) are free radicals thought to mediate the neurotoxic effects of several neurodegenerative disorders.In the central nervous system,ROS can also trigger a phenotypic switch in both astrocytes and microglia that further aggravates neurodegeneration,termed reactive gliosis.Negative regulators of ROS,such as mitochondrial uncoupling protein 2(UCP2) are neuroprotective factors that decrease neuron loss in models of stroke,epilepsy,and parkinsonism.However,it is unclear whether UCP2 acts purely to prevent ROS production,or also to prevent gliosis.In this review article,we discuss published evidence supporting the hypothesis that UCP2 is a neuroprotective factor both through its direct effects in decreasing mitochondrial ROS and through its effects in astrocytes and microglia.A major effect of UCP2 activation in glia is a change in the spectrum of secreted cytokines towards a more anti-inflammatory spectrum.There are multiple mechanisms that can control the level or activity of UCP2,including a variety of metabolites and micro RNAs.Understanding these mechanisms will be key to exploitingthe protective effects of UCP2 in therapies for multiple neurodegenerative conditions.展开更多
AIM:To develop a sensitive assay for screening compounds against hepatitis C virus (HCV).METHODS:The proteolytic cleavage of NS3/4A on enhanced yellow fluorescent protein (eYFP)-mitochondrial antiviral signaling prote...AIM:To develop a sensitive assay for screening compounds against hepatitis C virus (HCV).METHODS:The proteolytic cleavage of NS3/4A on enhanced yellow fluorescent protein (eYFP)-mitochondrial antiviral signaling protein (MAVS) was examined by reporter enzyme secreted placental alkaline phosphatase (SEAP),which enabled us to perform ongoing monitoring of anti-HCV drugs through repeated chemiluminescence.Subcellular localization of eYFP-MAVS was assessed by fluorescence microscopy.Cellular localization and protein levels were examined by Western blotting.RESULTS:HCV NS3/4A protease cleaved eYFP-MAVSfrom mitochondria to block the activation of interferon (IFN)-β promoter,thus resulting in downregulation of SEAP activity.The decrease in SEAP activity was proportional to the dose of active NS3/4A protease.Also this reporter assay was used to detect anti-HCV activity of IFN-α and cyclosporine A.CONCLUSION:Our data show that this reporter system is a sensitive and quantitative reporter of anti-HCV inhibitors.This system will constitute a new tool to allow the efficient screening of HCV inhibitors.展开更多
Chloroplasts and mitochondria contain a family of putative preprotein and amino acid transporters designated PRAT. Here, we analyzed the role of two previously characterized PRAT protein family members, encoded by At3...Chloroplasts and mitochondria contain a family of putative preprotein and amino acid transporters designated PRAT. Here, we analyzed the role of two previously characterized PRAT protein family members, encoded by At3g49560 (HP30) and At5g24650 (HP30-2), in planta using a combination of genetic, cell biological and biochemical approaches. Expression studies and green fluorescent protein tagging identified HP30-2 both in chloroplasts and mitochondria, whereas HP30 was located exclusively in chloroplasts. Biochemical evidence was obtained for an association of mitochondrial HP30-2 with two distinct protein complexes, one containing the inner membrane translocase TIM22 and the other containing an alternative NAD(P)H dehydrogenase subunit (NDCI) implicated in a respiratory complex 1-1ike electron trans- port chain. Through its association with TIM22, HP30-2 is involved in the uptake of carrier proteins and other, hydrophobic membrane proteins lacking cleavable N H2-terminal presequences, whereas HP30-2's interaction with NDC1 may permit controlling mitochondrial biogenesis and activity.展开更多
Protein phosphorylation is a well-established post-translational mechanism that regulates protein functions and metabolic pathways.It is known that several plant mitochondrial proteins are phosphorylated in a reversib...Protein phosphorylation is a well-established post-translational mechanism that regulates protein functions and metabolic pathways.It is known that several plant mitochondrial proteins are phosphorylated in a reversible manner.However,the identities of the protein kinases/phosphatases involved in this mech-anism and their roles in the regulation of the tricarboxylic acid(TCA)cycle remain unclear.In this study,we isolated and characterized plants lacking two mitochondrially targeted phosphatases(Sal2 and PP2c63)along with pyruvate dehydrogenase kinase(PDK),Protein-protein interaction analysis,quantitative phos-phoproteomics,and enzymatic analyses revealed that PDK specifically regulates pyruvate dehydrogenase complex(PDC),while PP2c63 nonspecifically regulates PDC.When recombinant PP2c63 and Sal2 proteins were added to mitochondria isolated from mutant plants,protein-protein interaction and enzymatic analyses showed that PP2c63 directly phosphorylates and modulates the activity of PDC,while Sal2 only indirectly affects TCA cycle enzymes.Characterization of steady-state metabolite levels and fluxes in the mutant lines further revealed that these phosphatases regulate flux through the TCA cycle,and that altered metabolism in the sa/2 pp2c63 double mutant compromises plant growth.These results are discussed in the context of current models of the control of respiration in plants.展开更多
Early embryogenesis is the most fundamental developmental process in biology. Screening of ethyl methanesulfonate (EMS)-mutagenized populations of Arabidopsis thaliana led to the identification of a zygote-lethal mu...Early embryogenesis is the most fundamental developmental process in biology. Screening of ethyl methanesulfonate (EMS)-mutagenized populations of Arabidopsis thaliana led to the identification of a zygote-lethal mutant embryonic factor 19 (fac19) in which embryo development was arrested at the elongated zygote to octant stage. The number of endosperm nuclei decreased significantly in fac19 embryos. Genetic analysis showed fac19 was caused by a single recessive mutation with typical mendelian segregation, suggesting equal maternal and paternal contributions of FAC19 towards zygotic embryogenesis. Positional cloning showed that FAC19 encodes a putative mitochondrial protein with 16 conserved pentatricopeptide repeat (PPR) motifs. The fac19 mutation caused a conversion from hydrophilic serine located in a previously unknown domain to hydrophobic leucine. Crosses between FAC191fac19 and the T-DNA insertion mutants in the same gene failed to complement the fac19 defects, confirming the identity of the gene. This study revealed the critical importance of a PPR protein-mediated mitochondrial function in early embryogenesis.展开更多
Objective To review the current advances on the role of uncoupling protein (UCP) in the pathogenesis and progress of nonalcoholic fatty liver disease (NAFLD).Data sources A comprehensive search of the PubMed liter...Objective To review the current advances on the role of uncoupling protein (UCP) in the pathogenesis and progress of nonalcoholic fatty liver disease (NAFLD).Data sources A comprehensive search of the PubMed literature without restriction on the publication date was carried out using keywords such as UCP and NAFLD.Study selection Articles containing information related to NAFLD and UCP were selected and carefully analyzed.Results The typical concepts,up-to-date findings,and existing controversies of UCP2 in NAFLD were summarized.Besides,the effect of a novel subtype of UCP (hepatocellular down regulated mitochondrial carrier protein,HDMCP) in NAFLD was also analyzed.Finally,the concept that any mitochondrial inner membrane carrier protein may have,more or less,the uncoupling ability was reinforced.Conclusions Considering the importance of NAFLD in clinics and UCP in energy metabolism,we believe that this review may raise research enthusiasm on the effect of UCP in NAFLD and provide a novel mechanism and therapeutic target for NAFLD.展开更多
There is accumulating evidence to show that environmental stressors can regulate a variety of phenotypes in descendants through germline-mediated epigenetic inheritance. Studies of model organisms exposed to environme...There is accumulating evidence to show that environmental stressors can regulate a variety of phenotypes in descendants through germline-mediated epigenetic inheritance. Studies of model organisms exposed to environmental cues(e.g., diet, heat stress, toxins) indicate that altered DNA methylations, histone modifications, or non-coding RNAs in the germ cells are responsible for the transgenerational effects. In addition,it has also become evident that maternal provision could provide a mechanism for the transgenerational inheritance of stress adaptations that result from ancestral environmental cues. However, how the signal of environmentally-induced stress response transmits from the soma to the germline, which may influence offspring fitness, remains largely elusive. Small RNAs could serve as signaling molecules that transmit between tissues and even across generations. Furthermore, a recent study revealed that neuronal mitochondrial perturbations induce a transgenerational induction of the mitochondrial unfolded protein response mediated by a Wnt-dependent increase in mitochondrial DNA levels. Here, we review recent work on the molecular mechanism by which parental experience can affect future generations and the importance of soma-to-germline signaling for transgenerational inheritance.展开更多
Mitochondria are the central hub for many metabolic processes,including the citric acid cycle,oxidative phosphorylation,and fatty acid oxidation.Recent studies have identified a new mitochondrial protein family,Fam210...Mitochondria are the central hub for many metabolic processes,including the citric acid cycle,oxidative phosphorylation,and fatty acid oxidation.Recent studies have identified a new mitochondrial protein family,Fam210,that regulates bone metabolism and red cell development in vertebrates.The model organism Caenorhabditis elegans has a Fam210 gene,y56a3a.22,but it lacks both bones and red blood cells.In this study,we report that Y56A3A.22 plays a crucial role in regulating mitochondrial protein homeostasis and reproduction.The nematode y56a3a.22 is expressed in various tissues,including the intestine,muscle,hypodermis,and germline,and its encoded protein is predominantly localized in mitochondria.y56a3a.22 deletion mutants are sterile owing to impaired oogenesis.Loss of Y56A3A.22 induced mitochondrial unfolded protein response(UPRmt),which is mediated through the ATFS-1-dependent pathway,in tissues such as the intestine,germline,hypodermis,and vulval muscle.We further show that infertility and UPRmt induces by Y56A3A.22 deficiency are not attributed to systemic iron deficiency.Together,our study reveals an important role of Y56A3A.22 in regulating mitochondrial protein homeostasis and oogenesis and provides a new genetic tool for exploring the mechanisms regulating mitochondrial metabolism and reproduction as well as the fundamental role of the Fam210 family.展开更多
基金supported by the National Natural Science Foundation of China,No.30960520the Natural Science Foundation of Inner Mongolia Autonomous Region of China,No.2016MS0837
文摘Glycosides of Cistanche(GC)is a preparation used extensively for its neuroprotective effect against neurological diseases,but its mechanisms of action remains incompletely understood.Here,we established a bilateral common carotid artery occlusion model of vascular dementia in rats and injected the model rats with a suspension of GC(10 mg/kg/day,intraperitoneally)for 14 consecutive days.Immunohistochemistry showed that GC significantly reduced p-tau and amyloid beta(Aβ)immunoreactivity in the hippocampus of the model rats.Proteomic analysis demonstrated upregulation of mitochondrial precursor protein and downregulation of keratin type II cytoskeletal6A after GC treatment compared with model rats that had received saline.Western blot assay confirmed these findings.Our results suggest that the neuroprotective effect of GC in vascular dementia occurs via the promotion of neuronal cytoskeleton regeneration.
文摘The B-cell lymphoma 2 (Bcl2) family of proteins participates in cell death or survival through a mitochondrial pathway. The pro-apoptotic members of the Bcl2 family such as Bim, Bid, Bax and Bak trigger cell death by contributing to the enhancement of mitochondrial outer membrane permeabil- ity to pro-apoptotic factors such as cytochrome c, with the subsequent activation of caspases. The anti-apoptotic mem- bers, such as B-cell lymphoma-extra large (Bd-xL), block the pro-apoptotic Bcl2 members and prevent cell death. Bcl-xL is abundantly expressed during development and in mature neurons, suggesting that it plays a role in protection from death from untoward events occurring in adult life such as ischemia, inflammation or trauma. When these neurotoxic in- sults occur, Bcl-xL translocates to mitochondria and prevents activation and homo-oligomerization of pro-apoptotic family members such Bax and Bak. Numerous studies have shown pro-survival roles for Bcl-xL in adult neurons using various models; nevertheless, the role of Bcl-xL outside of the field of neuronal death, i.e., in adult neuronal growth, excitability or synaptic plasticity, has not been studied in depth.
基金Supported by the Key Projects of Natural Science Foundation of Ningxia,No.2020AAC02020the Funds of Ningxia Medical University,No.XY201808.
文摘The mitochondrial unfolded protein response(UPRmt)is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress.Under physiological and pathological conditions,the UPRmt is the key to maintaining intracellular homeostasis and proteostasis.Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development,metabolism,and immune processes.UPRmt dysfunction leads to a variety of pathologies,including cancer,inflammation,neurodegenerative disease,metabolic disease,and immune disease.Stem cells have a special ability to selfrenew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues.These cells are involved in development,tissue renewal,and some disease processes.Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported,the roles of the UPRmt in stem cells are not fully understood.The roles and functions of the UPRmt depend on stem cell type.Therefore,this paper summarizes the potential significance of the UPRmt in embryonic stem cells,tissue stem cells,tumor stem cells,and induced pluripotent stem cells.The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.
基金Supported by Ningxia Natural Science Foundation,No.2020AAC03130Ningxia Medical University Project,No.XM2020005.
文摘BACKGROUND Gastric carcinoma(GC)is a common gastrointestinal malignancy worldwide.Based on the cancer-related mortality,the current prevention and treatment strategies for GC still show poor clinical results.Therefore,it is important to find effective drug treatment targets.AIM To explore the mechanism by which 18β-glycyrrhetinic acid(18β-GRA)regulates mitochondrial ribosomal protein L35(MRPL35)related signal proteins to inhibit the proliferation of GC cells.METHODS Cell counting kit-8 assay was used to detect the effects of 18β-GRA on the survival rate of human normal gastric mucosal cell line GES-1 and the proliferation of GC cell lines MGC80-3 and BGC-823.The apoptosis and cell cycle were assessed by flow cytometry.Cell invasion and migration were evaluated by Transwell assay,and cell scratch test was used to detect cell migration.Furthermore,a tumor model was established by hypodermic injection of 2.5×106 BGC-823 cells at the selected positions of BALB/c nude mice to determine the effect of 18β-GRA on GC cell proliferation,and quantitative reverse transcription-polymerase chain reaction(qRT-PCR)was used to detect MRPL35 expression in the engrafted tumors in mice.We used the term tandem mass tag(TMT)labeling combined with liquid chromatography–tandem mass spectrometry to screen for differentially expressed proteins(DEPs)extracted from GC cells and control cells after 18β-GRA intervention.A detailed bioinformatics analysis of these DEPs was performed,including Gene Ontology annotation and enrichment analysis,Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis,and so on.Moreover,STRING database(https://string-db.org/)was used to predict proteinprotein interaction(PPI)relationships and Western blot was used to detect the expression of proteins of interest in GC cells.RESULTS The results indicated that 18β-GRA could inhibit the proliferation of GC cells in a dose-and timedependent manner.It could induce GC cell apoptosis and arrest the cell cycle at G0/G1 phase.The proportion of cells arrested at S phase decreased with the increase of 18-GRA dose,and the migration and invasiveness of GC cells were inhibited.The results of animal experiments showed that 18β-GRA could inhibit tumor formation in BALB/c nude mice,and qRT-PCR results showed that MRPL35 expression level was significantly reduced in the engrafted tumors in mice.Using TMT technology,609 DEPs,among which 335 were up-regulated and 274 were down-regulated,were identified in 18β-GRA intervention compared with control.We found that the intervention of 18β-GRA in GC cells involved many important biological processes and signaling pathways,such as cellular processes,biological regulation,and TP53 signaling pathway.Notably,after the drug intervention,MRPL35 expression was significantly down-regulated(P=0.000247),TP53 expression was up-regulated(P=0.02676),and BCL2L1 was down-regulated(P=0.01699).Combined with the Retrieval of Interacting Genes/Proteins database,we analyzed the relationship between MRPL35,TP53,and BCL2L1 signaling proteins,and we found that COPS5,BAX,and BAD proteins can form a PPI network with MRPL35,TP53,and BCL2L1.Western blot analysis confirmed the intervention effect of 18β-GRA on GC cells,MRPL35,TP53,and BCL2L1 showed dose-dependent up/down-regulation,and the expression of COPS5,BAX,and BAD also increased/decreased with the change of 18β-GRA concentration.CONCLUSION 18β-GRA can inhibit the proliferation of GC cells by regulating MRPL35,COPS5,TP53,BCL2L1,BAX,and BAD.
基金Supported by grants to G. S.: the National Key R&D Program of China (2019YFA0802600 and 2018YFC1004500)the National Natural Science Foundation of China (31725016, 31930019, and 91940303)and the Strategic Priority Research Program (Pilot Study) “Biological basis of aging and therapeutic strategies” of the Chinese Academy of Sciences (XDPB10).
文摘Mammalian mitochondria have small genomes encoding very limited numbers of proteins.Over one thousand proteins and noncoding RNAs encoded by the nuclear genome must be imported from the cytosol into the mitochondria.Here,we report the identification of hundreds of circular RNAs(mecciRNAs)encoded by the mitochondrial genome.We provide both in vitro and in vivo evidence to show that mecciRNAs facilitate the mitochondrial entry of nuclear-encoded proteins by serving as molecular chaperones in the folding of imported proteins.Known components involved in mitochondrial protein and RNA importation,such as TOM40 and PNPASE,interact with mecciRNAs and regulate protein entry.The expression of mecciRNAs is regulated,and these transcripts are critical for the adaption of mitochondria to physiological conditions and diseases such as stresses and cancers by modulating mitochondrial protein importation.mecciRNAs and their associated physiological roles add categories and functions to the known eukaryotic circular RNAs and shed novel light on the communication between mitochondria and the nucleus.
文摘Reactive oxygen species(ROS) are free radicals thought to mediate the neurotoxic effects of several neurodegenerative disorders.In the central nervous system,ROS can also trigger a phenotypic switch in both astrocytes and microglia that further aggravates neurodegeneration,termed reactive gliosis.Negative regulators of ROS,such as mitochondrial uncoupling protein 2(UCP2) are neuroprotective factors that decrease neuron loss in models of stroke,epilepsy,and parkinsonism.However,it is unclear whether UCP2 acts purely to prevent ROS production,or also to prevent gliosis.In this review article,we discuss published evidence supporting the hypothesis that UCP2 is a neuroprotective factor both through its direct effects in decreasing mitochondrial ROS and through its effects in astrocytes and microglia.A major effect of UCP2 activation in glia is a change in the spectrum of secreted cytokines towards a more anti-inflammatory spectrum.There are multiple mechanisms that can control the level or activity of UCP2,including a variety of metabolites and micro RNAs.Understanding these mechanisms will be key to exploitingthe protective effects of UCP2 in therapies for multiple neurodegenerative conditions.
基金Supported by The Natural Science Foundation of China,No.30600330,No.30671842,No.30672488,No.30700475,No.30771919and No.30700757the National High Technology Research and Development Program of China,No.2008AA02Z132+1 种基金Beijing Municipal Natural Science Foundation,No.5082016Mega-projects of Science Research for the 11th Five-Year Plan,No.2009ZX10004-4001
文摘AIM:To develop a sensitive assay for screening compounds against hepatitis C virus (HCV).METHODS:The proteolytic cleavage of NS3/4A on enhanced yellow fluorescent protein (eYFP)-mitochondrial antiviral signaling protein (MAVS) was examined by reporter enzyme secreted placental alkaline phosphatase (SEAP),which enabled us to perform ongoing monitoring of anti-HCV drugs through repeated chemiluminescence.Subcellular localization of eYFP-MAVS was assessed by fluorescence microscopy.Cellular localization and protein levels were examined by Western blotting.RESULTS:HCV NS3/4A protease cleaved eYFP-MAVSfrom mitochondria to block the activation of interferon (IFN)-β promoter,thus resulting in downregulation of SEAP activity.The decrease in SEAP activity was proportional to the dose of active NS3/4A protease.Also this reporter assay was used to detect anti-HCV activity of IFN-α and cyclosporine A.CONCLUSION:Our data show that this reporter system is a sensitive and quantitative reporter of anti-HCV inhibitors.This system will constitute a new tool to allow the efficient screening of HCV inhibitors.
基金supported by the Chaire d’Excellence Program of the French Ministry of National Education and Research(to CR)
文摘Chloroplasts and mitochondria contain a family of putative preprotein and amino acid transporters designated PRAT. Here, we analyzed the role of two previously characterized PRAT protein family members, encoded by At3g49560 (HP30) and At5g24650 (HP30-2), in planta using a combination of genetic, cell biological and biochemical approaches. Expression studies and green fluorescent protein tagging identified HP30-2 both in chloroplasts and mitochondria, whereas HP30 was located exclusively in chloroplasts. Biochemical evidence was obtained for an association of mitochondrial HP30-2 with two distinct protein complexes, one containing the inner membrane translocase TIM22 and the other containing an alternative NAD(P)H dehydrogenase subunit (NDCI) implicated in a respiratory complex 1-1ike electron trans- port chain. Through its association with TIM22, HP30-2 is involved in the uptake of carrier proteins and other, hydrophobic membrane proteins lacking cleavable N H2-terminal presequences, whereas HP30-2's interaction with NDC1 may permit controlling mitochondrial biogenesis and activity.
基金the Max Planck Society(A.R.F.and Y.Z)and the European Union's Horizon 2020 Research and Innovation program,project PlantaSYST(A.R.F.and Y.Z.)Deutsche For-schungsgemeinschaft(FI 1655/3-1 and INST 211/744-1 FUGG for I.F).
文摘Protein phosphorylation is a well-established post-translational mechanism that regulates protein functions and metabolic pathways.It is known that several plant mitochondrial proteins are phosphorylated in a reversible manner.However,the identities of the protein kinases/phosphatases involved in this mech-anism and their roles in the regulation of the tricarboxylic acid(TCA)cycle remain unclear.In this study,we isolated and characterized plants lacking two mitochondrially targeted phosphatases(Sal2 and PP2c63)along with pyruvate dehydrogenase kinase(PDK),Protein-protein interaction analysis,quantitative phos-phoproteomics,and enzymatic analyses revealed that PDK specifically regulates pyruvate dehydrogenase complex(PDC),while PP2c63 nonspecifically regulates PDC.When recombinant PP2c63 and Sal2 proteins were added to mitochondria isolated from mutant plants,protein-protein interaction and enzymatic analyses showed that PP2c63 directly phosphorylates and modulates the activity of PDC,while Sal2 only indirectly affects TCA cycle enzymes.Characterization of steady-state metabolite levels and fluxes in the mutant lines further revealed that these phosphatases regulate flux through the TCA cycle,and that altered metabolism in the sa/2 pp2c63 double mutant compromises plant growth.These results are discussed in the context of current models of the control of respiration in plants.
基金supported by the National Natural Science Foundation of China (30625018 and 30821007)CAS/SAFEA International Partnership Program for Creative Research Teams (20090491019)CAS 100-Talent Projects of China
文摘Early embryogenesis is the most fundamental developmental process in biology. Screening of ethyl methanesulfonate (EMS)-mutagenized populations of Arabidopsis thaliana led to the identification of a zygote-lethal mutant embryonic factor 19 (fac19) in which embryo development was arrested at the elongated zygote to octant stage. The number of endosperm nuclei decreased significantly in fac19 embryos. Genetic analysis showed fac19 was caused by a single recessive mutation with typical mendelian segregation, suggesting equal maternal and paternal contributions of FAC19 towards zygotic embryogenesis. Positional cloning showed that FAC19 encodes a putative mitochondrial protein with 16 conserved pentatricopeptide repeat (PPR) motifs. The fac19 mutation caused a conversion from hydrophilic serine located in a previously unknown domain to hydrophobic leucine. Crosses between FAC191fac19 and the T-DNA insertion mutants in the same gene failed to complement the fac19 defects, confirming the identity of the gene. This study revealed the critical importance of a PPR protein-mediated mitochondrial function in early embryogenesis.
基金This study was supported by grants from the National Natural Science Foundation of China (No. 81000169, No. 81100277, No. 81200284, No. 81230012), the Excellent Young Investigator Foundation of Health Bureau of Zhejiang Province (No. 2010QNA011), the Excellent Young Investigator Natural Science Foundation of Zhejiang province (No. R2110159), and the Project of Zhejiang Traditional Chinese Medicine Administration Bureau (No. 2010ZA065).
文摘Objective To review the current advances on the role of uncoupling protein (UCP) in the pathogenesis and progress of nonalcoholic fatty liver disease (NAFLD).Data sources A comprehensive search of the PubMed literature without restriction on the publication date was carried out using keywords such as UCP and NAFLD.Study selection Articles containing information related to NAFLD and UCP were selected and carefully analyzed.Results The typical concepts,up-to-date findings,and existing controversies of UCP2 in NAFLD were summarized.Besides,the effect of a novel subtype of UCP (hepatocellular down regulated mitochondrial carrier protein,HDMCP) in NAFLD was also analyzed.Finally,the concept that any mitochondrial inner membrane carrier protein may have,more or less,the uncoupling ability was reinforced.Conclusions Considering the importance of NAFLD in clinics and UCP in energy metabolism,we believe that this review may raise research enthusiasm on the effect of UCP in NAFLD and provide a novel mechanism and therapeutic target for NAFLD.
基金supported by the National Key R&D Program of China(2017YFA0506400)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39000000)+1 种基金the National Natural Science Foundation of China(31930023,31771333)supported by the China National Postdoctoral Program for Innovative Talents(BX2021356)。
文摘There is accumulating evidence to show that environmental stressors can regulate a variety of phenotypes in descendants through germline-mediated epigenetic inheritance. Studies of model organisms exposed to environmental cues(e.g., diet, heat stress, toxins) indicate that altered DNA methylations, histone modifications, or non-coding RNAs in the germ cells are responsible for the transgenerational effects. In addition,it has also become evident that maternal provision could provide a mechanism for the transgenerational inheritance of stress adaptations that result from ancestral environmental cues. However, how the signal of environmentally-induced stress response transmits from the soma to the germline, which may influence offspring fitness, remains largely elusive. Small RNAs could serve as signaling molecules that transmit between tissues and even across generations. Furthermore, a recent study revealed that neuronal mitochondrial perturbations induce a transgenerational induction of the mitochondrial unfolded protein response mediated by a Wnt-dependent increase in mitochondrial DNA levels. Here, we review recent work on the molecular mechanism by which parental experience can affect future generations and the importance of soma-to-germline signaling for transgenerational inheritance.
基金the Caenorhabditis Genetics Center(CGC,funded by NIH Office of Research Infrastructure Programs P40 OD010440)the National Bioresource Project+3 种基金supported by funding from the Zhejiang Natural Science Foundation(LR17C110001)the National Natural Science Foundation of China(31871200 and 31371435)the National Key Basic Research Program of China(2015CB150300)to C.Cthe National Natural Science Foundation of China(31671522,31972891 and 91754111)to S.X
文摘Mitochondria are the central hub for many metabolic processes,including the citric acid cycle,oxidative phosphorylation,and fatty acid oxidation.Recent studies have identified a new mitochondrial protein family,Fam210,that regulates bone metabolism and red cell development in vertebrates.The model organism Caenorhabditis elegans has a Fam210 gene,y56a3a.22,but it lacks both bones and red blood cells.In this study,we report that Y56A3A.22 plays a crucial role in regulating mitochondrial protein homeostasis and reproduction.The nematode y56a3a.22 is expressed in various tissues,including the intestine,muscle,hypodermis,and germline,and its encoded protein is predominantly localized in mitochondria.y56a3a.22 deletion mutants are sterile owing to impaired oogenesis.Loss of Y56A3A.22 induced mitochondrial unfolded protein response(UPRmt),which is mediated through the ATFS-1-dependent pathway,in tissues such as the intestine,germline,hypodermis,and vulval muscle.We further show that infertility and UPRmt induces by Y56A3A.22 deficiency are not attributed to systemic iron deficiency.Together,our study reveals an important role of Y56A3A.22 in regulating mitochondrial protein homeostasis and oogenesis and provides a new genetic tool for exploring the mechanisms regulating mitochondrial metabolism and reproduction as well as the fundamental role of the Fam210 family.